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Original Studies |
Service of Endocrinology (E.C., L.B., N.G.-P.), Department of Biochemistry (J.-G.L.), Faculty of Medicine, University of Sherbrooke, Sherbrooke, Québec, Canada J1H 5N4
Address all correspondence and requests for reprints to: Dr. Nicole Gallo-Payet, Service of Endocrinology, Faculty of Medicine, University of Sherbrooke, 3001 12th Avenue North, Sherbrooke, Québec, Canada J1H 5N4. E-mail: n.gallo{at}courrier.usherb.ca
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Abstract |
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1 was found mainly in the definitive
zone and the 2-subunit mainly in the transitional zone, whereas
integrin 3 (which binds both fibronectin and laminin) was detected
only in the fetal zone. The ß2-subunit was observed solely in
chromaffin cells. Such specific gradients of integrin and MEC component
expression suggest that the extracellular environment does play a
definite role during adrenal gland development. Indeed, compared with
that in untreated plastic dishes, ACTH stimulation of
dehydroepiandrosterone sulfate and cortisol was enhanced by
collagen IV. In addition, fibronectin enhanced dehydroepiandrosterone
sulfate but decreased cortisol secretion, compared with collagen IV
substrates. These results provide fundamental insight into the
contribution of the microenvironment in cellular processes leading to
fetal adrenal gland development. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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This particular morphological developmental pattern, observed in primate fetal adrenal glands, is tightly associated with its functional development and properties (2). Because the fetal zone primarily expresses the enzyme P450C17, steroidogenesis is oriented toward DHEAS production (10). On approaching term, the transitional zone progressively becomes immunoreactive for 3ß-hydroxysteroid dehydrogenase (3ß-HSD) and begins to produce cortisol (11). In summary, fetal adrenal gland maturation in humans involves zone-regulated proliferation, differentiation, and apoptosis, together with zone-regulated expression of steroidogenic enzymes, as well as migration from the periphery to the central portion of the gland.
Several studies indicate that the extracellular microenvironment can orchestrate functions such as proliferation, migration, differentiation (12, 13, 14), and even anoikis (15). These observations suggest that the extracellular matrix (ECM) and its receptors, integrins, could play an important role during fetal development (16) and in tissue remodeling (17). However, there is little data concerning cellular functions associated with expression of ECM components and integrins in the adrenal gland. The only available studies involve expression of some ECM substrates and thrombospondins in the bovine adult adrenal cortex. As reviewed recently by Feige et al. (18), a differential expression of fibronectin and laminin is observed from the periphery to the center of the gland, which is associated with cell-specific activities. For example, laminin stimulates chemotaxis and haptotaxis of adrenocortical cells (19), whereas a cocktail of various ECM components (Matrigel) potentiates hormone-stimulated expression of the steroidogenic enzymes (20).
The aim of the present study was thus to identify and localize some of the most common ECM components, namely laminin, fibronectin, and the nonfibrillar collagen IV, as well as some of their receptors of the integrin family, in the intact human fetal adrenal gland. These results should provide fundamental insight into the contribution of the microenvironment in cellular processes leading to fetal adrenal development.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The chemicals used in the present study were obtained from the
following sources: Tissue-Tek embedding medium for frozen tissue
specimens from Miles (Elkhart, IN); gelatin from Fisher Scientific(Nepean, Ontario, Canada). Primary
antibodies used in this work were monoclonal antibodies directed
against human collagen IV, chromogranin A, and human - and
ß-integrin screening kits (ECM430 and ECM440, respectively), all from
Chemicon (Temecula, CA), as well as fibronectin (clone FN15) from
Sigma-Aldrich Corp. (Oakville, Ontario, Canada). An
antilaminin rabbit polyclonal antibody (Sigma-Aldrich Corp.) was also used. Vectashield mounting medium was
from Vector Laboratories, Inc. (Burlingame, CA);
fluorescein isothiocyanate (FITC)-conjugated antimouse or antirabbit
antibodies, from Roche Molecular Biochemicals
(Montréal, Québec, Canada). Deoxyribonuclease was purchased
from Sigma (St. Louis, MO) and collagenase,
MEM-Eagle-Medium, and OPTI-MEM from Life Technologies, Inc. (Burlington, Ontario, Canada). Matrix-coated dishes (collagen
IV, fibronectin, laminin) were from BD-VWR Canlab (Ville Mont-Royal,
Québec, Canada). Anticortisol antibody for RIA was from ICN Biochemicals, Inc. (Costa Mesa, CA); antidehydroepiandrosterone
(DHEA) and antidehydroepiandrosterone sulfate
(DHEAS) antibody were kindly provided by Dr. Alain Bélanger
(Laboratoire d’Endocrinologie Moléculaire, Center de recherche
du CHUL, Ste-Foy, Québec, Canada). Tritiated cortisol was from
Amersham Pharmacia Biotech (Oakville, Ontario, Canada);
tritiated DHEA and DHEAS were from NEN Life Science Products-DuPont (Missauga, Ontario, Canada). ACTH 1–24 peptide
(Cortrosyn) was from Organon (Toronto, Ontario, Canada),
and angiotensin (Ang) II was from Bachem California, Inc.
(Marina Delphen, CA). All other chemicals were of A-grade purity.
Retrieval and preparation of glands
Fetal adrenal glands were obtained from fetuses between 14 and 21 weeks old (post fertilization) at the time of therapeutic abortion. Fetal ages were estimated by foot length and time after last menstruation, according to Streeter et al. (21). The project was approved by the human subject review committee of our institution. After retrieval, glands were cleansed of fat in MEM and were either processed immediately for cellular preparation or were included in a cryoprotectant (OCT Tissue Tek), frozen in liquid nitrogen, and stored at -80 C until use. Sections of 3–5 µm were prepared and used for immunofluorescence detection.
Immunofluorescence studies
Tissue sections were processed according to the method of Basora
et al. (22). In brief, sections were fixed in
100% cold ethanol for 10 min at -20 C and then progressively
rehydrated with successive Hanks’ buffer saline (HBS: 130
mM NaCl, 3.5 mM KCl, 1.8
mM MgCl2 2.5
mM NaHCO3, and 5
mM HEPES) washings. Autofluorescence was
prevented by incubating sections in glycine (0.01
M) in HBS for 30 min. Nonspecific sites were
blocked with 10% nonfat milk for 30 min. The sections were then
incubated with the primary antibody either directed against laminin
(dilution 1:100), fibronectin (dilution 1:500), collagen IV (dilution
1:500), or different - and ß-integrin subunits (dilution 1:250),
for 1 h at room temperature, in a humidified atmosphere. After
washings with HBS, the sections were incubated with the secondary
FITC-coupled antibody (either antimouse, antirabbit, or antirat) in a
blocking solution containing 0.05% BSA, for 1 h at room
temperature, in a humidified atmosphere. After washing, sections were
stained with a 0.01% Evan’s Blue solution, which allows visualization
of the cellular composition of the whole gland when examined with a
rhodamine filter. After two subsequent washings, slides were mounted
with Vectashield mounting medium and examined under a fluorescence
microscope [Leica Corp. (Québec, Canada)
Reichart Polyvar 2 or Nikon (Missauga, Ontario,
Canada) Ellipse 300] equipped with B-1E FITC and G-2A rhodamine
specific filters. In all cases, no specific staining was observed when
primary antibodies were replaced by rabbit preimmune serum (data not
shown). Note that the illustrations (except one, see Fig. 3C
) were
taken with the same camera settings for contrast and brightness.
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Glands were processed as described previously (5, 23). Whole tissues were used for cell preparation, without separation of fetal zone, neocortex, or chromaffin cells. Briefly, small pieces of tissue (1–2 mm3) were dissociated with collagenase (2 mg/mL) and deoxyribonuclease (25 µg/mL) in Eagle’s MEM containing 2% antibiotics. After three incubation periods of 20 min, cells were dissociated, filtered, and centrifuged for 10 min at 100 x g. The cell pellet was suspended in OPTI-MEM medium containing 2% FCS and antibiotics. Cells were plated at a density of about 1 x 105 in 35 mm, either on plastic Petri dishes or in dishes coated with various matrices including collagen IV, fibronectin, or laminin. Cells were grown for 3 days in a humidified atmosphere of 95% air-5% CO2, at 37 C, and either stimulated with ACTH (10-9 M) or vehicle every 24 h after an initial 24-h resting period. The culture medium was collected every 24 h and stored at -20 C until assayed for steroid secretion. DHEA, DHEAS, and cortisol were determined by RIA using specific antisera and tritiated steroid as tracer. The data are presented as means ± SEM from three independent fetuses. Statistical P values were obtained from Dunnett’s tables, using the Bartlett’s test.
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Results |
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Cryo-sections from second-trimester adrenal glands were used to
immunolocalize the most common components of the ECM, i.e.
collagens, fibronectin, and laminin. Each of these glycoproteins
comprises a large family of proteins, collagen I being common to all
tissues and collagen IV found in the basement membranes of epithelial
cells (24, 25). We used antibodies raised against the
common portion of each of the proteins to be tested. Type IV collagen
was present, exhibiting the same level of expression throughout the
gland (Fig. 1A). Labeling was found in
the capsule and in large arrays penetrating the neocortex and the
adjacent fetal zone. Labeling was also visible as fibrillar structures
underlining sinusoid and capillaries (Fig. 1B), as shown by the
corresponding pattern of localization of the von Willerbrand factor (a
marker of endothelial cells) (Fig. 1C). Moreover, a very low level of
expression was found around each cell of the definitive zone (Fig. 1B).
In the fetal zone, labeling changed progressively from large ribs in
the external portion [Fig. 1, D (open arrow) and E] to a
more specific localization around each cell (arrow) in the
center of the gland (Fig. 1, F and G). Fibronectin was also detected,
but the overall pattern of expression was higher in the central portion
of the gland, compared with the periphery (Fig. 2A). Fibers were found in the capsule and
as columns penetrating the definitive zone and the adjacent fetal zone
(Fig. 2B). Some weak labeling could be seen around small groups of
neocortical cells (Fig. 2B); whereas, deeper in the gland, each cell
was clearly surrounded by fibronectin (Fig. 2C, arrow).
Laminin was also detected in the fetal adrenal gland; however, the
overall labeling is low, compared with collagen or fibronectin (Fig. 3A
, arrow). The highest
labeling is observed around small arteries in the capsule (Fig. 3B) and
around each cell of the transitional zone (Fig. 3, A and B). When
pictures of the fetal zone were analyzed with high magnification (Fig. 3C), a tiny labeling was also shown around each fetal cell, along with
a strong labeling at some points (arrows), which could be
focal adhesions or capillaries. Indeed, this micrograph was taken with
optimized camera settings because of the low level of laminin
expression in the fetal zone.
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Because ECM components bind to integrins to generate intracellular
signals, we then examined whether the most common candidates for
fibronectin, laminin, and collagen binding could be detected in
the human fetal adrenal gland. All integrins are dimers of - and
ß-chains, with the ß1-subunit being the most common (12, 13). Thus, ß1 could be considered as being ubiquitous. As
expected, all areas of the fetal adrenal gland were immunopositive for
the integrin subunit ß1, including small arteries in the capsule
(Fig. 4A, arrow). The
ß1-chain was expressed uniformly over cells of the definitive zone
(Fig. 4A) and of the fetal zone (Fig. 4B). Specific ß2 labeling was
also localized in the capsule and in islets of small cells (Fig. 5, A and C) dispersed throughout the
fetal cortex, with a higher concentration in the central portion of the
gland (Fig. 5A). Labeling of consecutive sections with chromogranin A
(a marker for secretory granules of chromaffin cells, Fig. 5, B and D)
confirmed the localization of the ß2-integrin on chromaffin cells
(Fig. 5, A and C).
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1 was present throughout the fetal
adrenal cortex, following a gradient of expression that was higher in
the definitive zone (Fig. 6A). Labeling
seemed to be localized at the surface of each cell from the definitive
(Fig. 6B), fetal zone (Fig. 6C) and chromaffin cells (Fig. 6D).
Integrin 2 was detected in both definitive and fetal zones (Fig. 7A), with a labeling higher in the
transitional zone (Fig. 7B) and around fetal cells (Fig. 7C). In
contrast, the 3-chain was absent in the definitive zone, despite a
clear signal in the capsule (Fig. 8A),
but was present in the fetal zone, with a more intense
expression at the center (Fig. 8B).
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To assess whether the distribution pattern of matrix and receptors
had a specific physiological significance, we measured
DHEA, DHEAS, and cortisol production by fetal adrenal
cells cultured on various matrices. Under control conditions, all of
the substrates tested (collagen IV, fibronectin, and laminin) enhanced
the basal level of C19-steroid secretion during the first 24 h of
culture (data not shown). After a 24-h resting period, cells were
stimulated with ACTH every 24 h for 2 days. As shown in Fig. 9A, the three matrices did not modify
significantly ACTH-stimulated DHEA secretion, compared
with plastic Petri dishes. In contrast, after 48 h of ACTH
stimulation, DHEAS and cortisol secretions were enhanced in cultures on
collagen IV (Fig. 9, B and C). Moreover, on fibronectin matrix,
ACTH-stimulated DHEAS was increased (Fig. 9B), although cortisol
stimulation was decreased (Fig. 9C).
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Discussion |
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1, and 2 distributed throughout the
gland, whereas ß2 and 3 had a more restricted pattern of
expression. Specific cellular responses are mediated by the recruitment of multiple cytoskeleton-associated proteins activated by binding of ECM components to their receptors, integrins (12, 13, 14). Most integrins recognize several ECM proteins; and these proteins, such as fibronectin, laminin, and collagens, can bind to several integrins (12, 13, 14). In the human fetal gland from the second trimester of gestation, we were able to identify collagen IV, the main component of basement membranes (24); fibronectin, a major protein involved in cell adhesion; and laminin, mainly implicated in migration. In addition to strong labeling in the capsule, collagen IV underlined capillaries and sinusoids, exhibiting a radial disposition and surrounding small groups of cells. This localization of collagen IV in basement membranes is compatible with the migration en masse of the medulla toward the central portion of the gland, recently reviewed by Wolkersdorfer et al. (26). As in the adult bovine adrenal gland (18), fibronectin was more abundant in the center than in the periphery, indicating that the gradient for fibronectin expression takes place early in gestation. The expression pattern of laminin was noticeably different from that seen for fibronectin and collagen IV. Stronger labeling was seen at the periphery, although some scattered labeling was also observed deeper in the gland. These observations are different from those of Pellerin et al. (19), who described a uniform distribution of laminin throughout the cortex of the bovine adrenal gland. For Pellerin et al., fibronectin and laminin are equally potent in promoting haptotaxis, suggesting that these molecules could drive cell migration from the periphery toward the center. Altogether, the most noticeable difference among collagen IV, fibronectin, and laminin was their gradient of expression from the periphery to the central region of the gland. All of these growth factors have been detected in the human fetal adrenal gland and shown to be involved in steroidogenesis (2).
From a hormonal point of view, some studies have shown that adrenocortical stimuli have opposite effects on fibronectin and laminin expression. ACTH and Ang II increase the synthesis of laminin (with ACTH being the most potent), whereas transforming growth factor ß (TGFß), fibroblast growth factor 2 (FGF-2), and insulin-like growth factor I decrease synthesis (19). The opposite was observed with fibronectin, whereby expression was stimulated by TGFß, FGF-2, and insulin-like growth factor I but decreased with ACTH and Ang II. However, in the adult cardiac tissue, several studies indicate that Ang II strongly stimulates MEC expression, in particular fibronectin and collagen (27, 28).
As mentioned previously, integrins comprise a large family of proteins
composed of two subunits, and ß, and each ß combination has
its own MEC binding specificity and signaling properties. We identified
the 1- and 2-subunits, as well as the ß1-subunits, in the whole
fetal adrenal gland. The overall pattern of expression for the
ß1-chain is not surprising, considering the involvement of this chain
in a wide range of /ß-dimers. Indeed, the ß1 cytoplasmic domain
is essential for integrin localization to sites of focal contacts,
essential for cell adhesion and required for survival. In contrast,
deletion of the -subunit decreases cell adhesion or cell motility,
indicating that specificity in cell function is associated with the
-subunit (13, 29). The integrins 1ß1 and 2ß1
are both high-affinity receptors for collagen IV (30). We
found 1 mostly in the definitive zone and 2 mainly in the
transitional zone. Together with the pattern observed for collagen IV,
the localization of 1, 2, and ß1 is again consistent with a
possible role in adhesion and migration (31, 32), both of
which are active processes during adrenal gland development. Recent
studies have shown that activation of 1ß1 after collagen/laminin
binding mediates cell contraction (32, 33), a process
which could contribute to migration. In addition, although collagen and
laminin are equally recognized by 2ß1, this association does not
lead to cell contraction, as observed with 1ß1, whereas both
integrins are involved in adhesion/migration (33).
Furthermore, in addition to migration, 2ß1 may induce apoptosis,
at least in T lymphocytes (34). The differential
expression of 1ß1 and 2ß1 may thus reflect a functional
difference between definitive and transitional zones.
The other two - and ß-subunits detected revealed a more specific
pattern of expression. Indeed, the 3-integrin subunit was not
detected in the definitive zone but was present in the fetal zone.
According to Kühn and Eble (30) and Arregui et
al. (35), this -chain, in association with the
ß1-subunit, is a weak affinity receptor for fibronectin. Considering
the fact that 5- and 4-subunits, both high-affinity receptors for
fibronectin when associated with ß1 (30), failed to be
identified in the fetal adrenal gland, 3ß1 could be considered as
the fibronectin receptor in the fetal zone, where laminin is poorly
expressed. The expression of a weak-affinity receptor for
fibronectin (3ß1) is in agreement with the model of cell migration
proposed for fetal adrenal gland development, more than a strong
adhesive complex such as 5ß1 with fibronectin (1, 2).
As stated previously, Ang II and TGFß modulate ECM composition, not
only in the adrenal gland but also in cardiac and vascular tissues
(27, 36). In addition, TGFß can up-regulate
1ß1-expression (32, 37), and actions of Ang II can be
modulated by matrix/receptors interactions (38). Moreover,
glucocorticoids decrease the expression of 2- and ß1-subunits
(39). Observations in adult tissues suggest that such
hormonal control may occur in both fetal and chromaffin cells of the
human fetal adrenal gland, where receptors are present. In regard to
our previous results indicating that the AT2
receptor of Ang II is highly expressed in the fetal zone during the
second trimester of gestation (23), a putative cross-talk
between fibronectin/3ß1/Ang II could be hypothesized. Some studies
have demonstrated interactions between fibronectin and Ang II
(38) that, as well as growth factors, share common
signaling pathways with integrins (MAP kinases, Phospho Inositol-3
Kinase) (40) and can also induce cytoskeletal
reorganization (5, 41, 42).
Interestingly, we also found a specific expression of the ß2-integrin subunit in chromaffin cells. These observations are the first to identify this subunit outside the lymphoid system. Indeed, this subunit has been extensively studied in hematopoietic cells and has been shown to be involved in migration and diapedesis of lymphocytes and leukocytes (43, 44). Considering that this integrin subunit is involved in migration and invasive processes, this subunit could play a role in the migration of chromaffin cells from the neural crest through the fetal cortex to colonize the center of the gland leading to the formation of the medulla.
In summary, we have identified 1-, 2-, and ß1-integrin subunits
throughout the fetal adrenal cortex, and these integrins recognize
collagen IV, fibronectin, and laminin. The gradient of fibronectin is
more important in the central portion of the gland than at the
periphery, whereas the opposite is true for laminin. We also identified
the integrin 3 (which can bind fibronectin) only in the fetal zone,
and ß2-integrin subunit solely in chromaffin cells.
This specific cell type expression, together with the gradient of
expression of MEC components, strongly suggests that cellular
environment plays a definite role during adrenal gland development.
This hypothesis is supported by results on steroid secretion. During
the second trimester of gestation, DHEAS is the major steroid
produced by the human fetal adrenal gland. At this stage, cortisol is
produced only marginally, using progesterone from the placenta rather
than its own precursors (for review, see 2). In fact,
3ß-HSD, the limiting steroidogenic enzyme for cortisol production, is
low or absent in the fetal cortex, whereas the other enzymes required
for steroidogenesis are present in the fetal cortex. Previous studies
have shown that ACTH induces the expression of 3ß-HSD in fetal
adrenal cells cultured on plastic Petri dishes. These cells were thus
able to produce cortisol (45). In the present study, we
showed that cultures on fibronectin increased ACTH-stimulated DHEAS,
but decreased that of cortisol, compared with collagen IV- or
plastic-coated dishes. In addition, collagen IV, which is present
throughout the gland, potentiates DHEAS and cortisol secretion by cells
cultured in the presence of ACTH. Considering the expression pattern of
fibronectin and 3-subunits, together with the well-accepted absence
of 3ß-HSD in the fetal zone, we can hypothesize that environmental
cues are involved in enzymatic expression. Corroborating these results,
Cheng and Hornsby (20) have shown that Matrigel can
promote P450 11ß-hydroxylase and P450 21-hydroxylase expression,
which otherwise decreases on long-term culture.
Figure 10 summarizes the present data,
in keeping with the particular morphology and functional activity of
the human fetal adrenal gland. There is no doubt that much work remains
to be done, with regard to the relationships between MEC components and
expression of steroidogenic enzymes. However, the present data opens
the door to a novel issue in the field of hormone action and coupling
in the adrenal gland. Specific characteristics of cell functions
associated with these MEC and their respective integrins remain to be
investigated, together with the modulation of their synthesis by ACTH,
Ang II, or growth factors. The role of Ang II will be of particular
interest because, during the second trimester of gestation, the
expression of the AT2 receptor is predominant
over that of AT1.
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Acknowledgments |
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Footnotes |
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2 A chercheur-boursier de carrière of FRSQ.
Received October 5, 2000.
Revised January 19, 2001.
Accepted January 24, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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7Bß1 expression in
human intestinal cells and enterocytic differentiation. Gastroenterology. 113:1510–1521.[CrossRef][Medline]
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integrin-mediated collagen matrix remodeling by rat mesangial cells is
differentially regulated by transforming growth factor-ß and
platelet-derived growth factor-BB. J Am Soc Nephrol. 10:779–789.1ß1 integrin is expressed during neointima formation in rat
arteries and mediates collagen matrix reorganization. J Clin
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2ß1
integrin inhibits Fas ligand expression and activation-induced cell
death in T cells in a focal adhesion kinase-dependent manner. Blood. 95:2044–2051.2-integrin expression in cytotrophoblasts by glucocorticoids. Endocrinology. 140:3904–3908.q/11-subunit with
cytoskeleton in adrenal glomerulosa cells: role in receptor-effector
coupling. Endocrinology. 138:3299–3307.-hydroxylase/17, 20-lyase, and 3ß-hydroxysteroid dehydrogenase
isomerase steroidogenic enzymes in human and rhesus monkey fetal
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